PHENTOLAMINE AND YOHIMBINE INHIBIT ATP-SENSITIVE K+ CHANNELS IN MOUSE PANCREATIC BETA-CELLS

1. The effects of phentolamine and yohimbine on adenosine 5'-triphosphate (ATP)-sensitive K+ channels were studied in normal mouse β-cells. 2. In the presence of 3 mM glucose, many ATP-sensitive K+ channels are open in the β-cell membrane. Under these conditions, phentolamine inhibited 86Rb efflux from the islets. This inhibition was faster with 100 than with 20 μM phentolamine but its steady-state magnitude was similar with both concentrations. Yohimbine (20-100 μM) also inhibited the efflux rate but was not as potent as phentolamine. 3. In the presence of 6 mM glucose, most ATP-sensitive K+ channels are closed in the β-cell membrane. Their opening by 100 μM diazoxide caused a marked acceleration of 86Rb efflux from the islets. This acceleration was almost entirely prevented by 20 μM phentolamine. It was barely affected by 20 μM yohimbine and reduced by 50% by 100 μM yohimbine. 4. ATP-sensitive K+ currents were studied in single β-cells by the whole cell patch-clamp technique. Phentolamine (20-100 μM) caused a progressive but almost complete and irreversible inhibition of the current. The effects of yohimbine were faster but smaller; the inhibition was still incomplete with 100 μM yohimbine. 5. The increase in ATP-sensitive K+ current produced by 100 μM diazoxide was prevented by 100 μM phentolamine but only partially attenuated by 100 μM yohimbine. 6. It is concluded that phentolamine inhibits ATP-sensitive K+ channels in pancreatic β-cells. This novel effect of phentolamine resembles that of hypoglycaemic sulphonylureas. It may account for previously unexplained effects of the drug. These observations also call for reinterpretation of many studies in which phentolamine was used as an allegedly specific blocker of α-adrenoceptors.